Hamilton_ Linda - State of AART

					       State of AART


 Linda Hamilton, MD, FRCSC
Atlantic Assisted Reproductive Therapies
           Halifax, Nova Scotia
Overview
• Incidence of Infertility
• Treatment options
• Issues in ART/IVF
  – Age
  – Elevated BMI
  – Multiple births
Incidence
• 85-90% conceive in 1 year
• 10-15% of couples affected

• Cumulative pregnancy rates
  – 3 months      50%
  – 6 months      72%
  – 12 months 85%
  – 24 months 93%
     • (n = 5574 women UK and USA)
Cycle Fertility


• Probability that intercourse at ovulation will
  result in pregnancy during any one cycle

• 20-25% in fertile couples less than 35 yo
Length of Infertility
 What are the possible fertility
 treatments???
• If open tubes and normal semen
 analysis (unexplained infertility or
 anovulation)

  –Clomiphene citrate
  –Controlled Ovarian Hyperstimulation
  –In Vitro Fertilization
  What are the possible fertility
  treatments???
• If tubes blocked
   –In Vitro Fertilization
• If poor sperm
   –In Vitro Fertilization AND
     Intracytoplasmic Sperm Injection (ICSI)
Superovulation




   Super levels of FSH
  Clomiphene citrate

• If open tubes and normal semen analysis
  – 100 mg Clomiphene is taken days 2 to 6 of cycle
  – Hopefully increases number of eggs produced
  – Does not make ‘better eggs’ just hopefully more
    eggs
  – Increases chances to 5 to 8% from a base line of
    3 to 5% in unexplained infertility
Clomiphene citrate
• Most experts would agree that if this has
  not ‘worked’ in 6 months that it is time to
  consider other options
• If used in anovulatory patients and causes
  ovulation then can continue longer
Controlled Ovarian Hyperstimulation

• If open tubes and normal semen function
    analysis
•   Usually Clomiphene days 2 to 6 of cycle
•   Injected FSH
•   Followed with blood work and ultrasound
•   Intrauterine insemination recommended
•   Success about 15 - 20% depending on
    age
Controlled Ovarian Hyperstimulation

• Side effects which resolve
   – Abdominal discomfort
   – Ovarian Hyperstimulation Syndrome (OHSS)


• Side effect that is ‘permanent’
   – Multiple birth rate
      • 30% multiples
      • Potential for higher order multiples
Ovarian Hyperstimulation Syndrome
(OHSS)

•   Occurs less than 1-2% patients
•   ‘Third space’ ascites
•   Short of breath
•   Admitted to hospital
    –   Measure daily weights, abdominal circumference
    –   Daily amount drink and urinate
    –   Anti-coagulant
    –   Occasionally need abdominal drained in radiology
In Vitro Fertilization +/- ICSI
• Only option if blocked tubes or poor sperm!!!

• Also used if open tubes and normal sperm
  functional analysis

• Aim is to stimulate numerous follicles which are
  fertilized in a ‘test tube’

• Embryos put back in uterus
IVF: A ‘NEW TECHNOLOGY’
• Louise Brown, world’s 1st IVF Baby, 1978
Superovulation




           Agonist




   Super levels of FSH
In Vitro Fertilization +/- ICSI

•   Injected FSH & LH (no clomiphene)
•   Ultrasound and bloodwork
•   Egg Retrieval
•   Embryo transfer

• Success varies with age
   CARTR Results 2007
Cycle Type         CARTR                        AART AART
                   # cycles Pregnancy (%)       #      Pregnancy (%)
                            (range by centre)   cycles
IVF/ICSI           9019     35%(20-51)          154    42%
All ages
Optimal: <35,DET   2581     51%(31-72)          34     68%
< 35               3903     43%(26-61)          64     55%
35-39              3569     33%(18-53)          69     35%
  40               1541     18%(6-36)           21     24%
Multiples                   31%(19-44)          24     36%
  AART Halifax Results 2007

                 All Transfers   Day 3   Day 5

Singletons       63.9%           60%     64.3%

Twins            32.8%           31.4%   32.1%

Triplets/Quads   6.6%            8.6%    3.6%
Issues in ART/IVF

• Increasing Maternal Age
‘Consult’

• 43 (or 44, or 45) yo trying for 6 months to
  conceive)
• Please see ASAP

• Suggest the ‘ASAP’ should be the 37 to 39
  yo trying for 6 months to 1 yr
Spontaneous fertility and Age
IVF success and Age




                      CDC ATLANTA 2006
IVF Success rate over 40 …..




                          CDC ATLANTA 2006
   CARTR Results 2007
Cycle Type         CARTR                        AART AART
                   # cycles Pregnancy (%)       #      Pregnancy (%)
                            (range by centre)   cycles
IVF/ICSI           9019     35%(20-51)          154    42%
All ages
Optimal: <35,DET   2581     51%(31-72)          34     68%
< 35               3903     43%(26-61)          64     55%
35-39              3569     33%(18-53)          69     35%
  40               1541     18%(6-36)           21     24%
Multiples                   31%(19-44)          24     36%
Pregnancy loss and age




                         CDC ATLANTA 2006
Aneuploidy and Age
Maternal Age   Risk of Trisomy   Risk all
               21 (liveborn)     chromosomal
                                 abnormalities
20             1/1667            1/526
35             1/385             1/204
40             1/106             1/65
41             1/82              1/51
42             1/64              1/40
43             1/50              1/32
44             1/38              1/25
45             1/30              1/20
46             1/23              1/15
Other options???

• Donor egg
• Adoption
• Living childfree
OWN VERSES DONOR EGGS




                  CDC ATLANTA 2006
Issues in ART/IVF

• Increased Body Mass Index
Incidence of extremes of BMI

• Overweight and obese in Canada 2004
  – 65.2% of adult males
  – 52.4% of adult females


• Obese, including morbidly obese
  – 23 % of Canadian men and women 2004
  – double the rate from 1978
  – N S 31 % higher than national average
Role of adipose tissue in female
reproduction
• Insulin resistance
• Hyperinsulinaemia
• Hyperandrogenemia
• Peripheral aromatization androgen to
  estrogens
• Decreased SHBG (sex hormone binding globulin)
• Central obesity highest risk
Fertility and Obesity

• Hassan et al Fertility and Sterility 2004
• 2112 consecutive pregnancies in UK
• Time to Pregnancy (TTP)
• Increase in TTP with Increased BMI P <0.001
• Twice as long on average 6.8 vs.. 13.3 mo
• Linear increase with increasing BMI
Obesity and IVF
•   Fedorcsak et al 2004 Hum Reprod
•   2660 couples (5019 cycles)
•   Controlled age, diagnosis
•   More cancelled cycles 2nd poor stimulation
•   Greater dose of FSH
•   Longer stimulation
•   Less eggs obtained
Fedorcsak et al 2004 Hum Reprod Cont’


• Increase BMI
  – Increase biochemical pregnancy
  – First trimester loss
  – Decreased live birth
     • 50.3% NW, 41% BMI > 30
  – Decreased cumulative live birth rate
Linsten et al 2005 Hum Reprod


• Higher live birth rate with BMI < 27
• 33% less live birth if BMI ≥ 27
• Greatest difference with unexplained
IVF and BMI

• Maheshwari et el 2007 Human Repro Update
• Meta-analysis
    – 20 studies
•   Lower likelihood of pregnancy
•   Increased miscarriage after IVF
•   Increased gonadotrophins
•   Decreased final E2, lower number of oocytes
Restricted assess to IVF

• British Fertility Society suggests
  – No IVF if BMI > 35
  – If BMI > 30 refer to weight loss program
• Many UK clinics have adopted this limit
Male Infertility and BMI

• Peripheral testosterone to estrogen
• Inhibition of hypothalamic-pituitary-
  gonadal axis
• Secondary hypogonadism
• Increased scrotal temperatures
Male Obesity and SA

•   Hammoud et al F & S 2008
•   Evaluated all couples seen infertility
•   Retrospective chart review
•   526 couples over 2 years
•   Excluded known male factor
Male Infertility and BMI




            Hammoud et al F & S 2008
Male Infertility and BMI




            Hammoud et al F & S 2008
Does Weight loss Help???

• Hollmann et al 1996
• 58 obese women with menstrual irreg.
• Measured AC glucose, insulin,
  androsteindione, dihydroxytestosterone
  and estradiol
• Group 1: weight loss group (n =35)
• Group 2: no weight loss program
Hollmann et al 1996


• Group 1
  – reduced calories
  – Minimum 40 gm protein/day
  – Increase activity
• Initial GTT then repeat at 10 % wgt loss
• Comparison with before and after wgt loss
 in same group
Hollmann et al 1996


•   80% improvement in menstrual function
•   6 spontaneous pregnancies in first 20 wks
•   Further 4 spontaneous pregnancies
•   Reduction in all blood values measured
•   Average BMI decreased from 35 to 31.6
•   Blood pressure decreased
Weight loss and fertility

•   Clark et al Hum Reprod 1998
•   Infertility > 2 years
•   BMI ≥ 30 kg/m2
•   Willing to forego fertility treatment for 6 mo
•   120 approached, 87 agreed, 67 completed
Weight loss and fertility

• Clark et al Hum Reprod 1998
• 6 month session :
  – Weight loss
  – 2 hrs/wk consist of 1 hr exercise, 1 hr
    instruction
  – Instruction varied: psychiatrist, dietitian, REI
  – Group cohesion and support encouraged
Clark et al Hum Reprod 1998
Clark et al Hum Reprod 1998
SUMMARY

• Obesity rates are increasing in Canada
• Obesity has a profound affect on basic
  fertility
• Increasing BMI is associated with
  decreased success in IVF
SUMMARY

• IVF cycles and increasing BMI
  – More drugs required
  – Increased failure to respond and cancellation
  – Longer stimulation period needed
  – Less oocytes retrieved
  – Poorer fertilization
  – Lower quality embryos
  – Fewer embryos to freeze
Summary
• Effect of age
  – Decrease fertility
  – Increased miscarriage rates
  – Decreased IVF success
  – Increased chromosomal abnormalities
• Elevated BMI
  – Fertility dramatically decreases
  – Increased miscarriage rates
  – Decreased IVF success
  – BUT ……
Summary
• AGE cannot be ‘fixed’
• Weight can be ‘fixed’
  – Infertility is a powerless situation for
    patients
  – Encouraging and supporting weight loss
    can give patients back some control
Issues in ART/IVF

• Multiple births
IVF: A ‘NEW TECHNOLOGY’

• Since 1978 ~ 3 million births world
    wide
•   Initial success was low but has
    increased dramatically over time
•   Success > 50% in optimal age group

• But at what cost???
Multiple Birth Rate in ART
• Spontaneous multiple rate
    – ~ 1.2% twins, < 1% higher order multiples
•   Assisted reproduction
    – Clomiphene
       • 8-10% twins, ~ 1-2% triplets
    – Controlled Ovarian Hyperstimulation
       • 30% multiple, potential for high order
         multiples
    – IVF
       • ~ 30-40% twins, ~ 5-7% triplets
Multiple Birth Risks
• Perinatal Mortality
    – 4 fold higher in twins
    – 6 - 9 fold higher in triplets
•   Perinatal Morbidity
    – Low birth weight, or very low birth weight
    – Increase risks associated with prematurity
    – Cerebral palsy
       • 3-7 fold increase in twins
       • > 10 fold in triplets (Peterson et al 1990)
2 vs. 3 Embryo Transfer???
• Templeton & Morris NEJM 1998
• 44,246 cycles in 25,240 women in UK
• Factors associated with success/multiples
  –   Age
  –   Duration of infertility
  –   Failed IVF attempts
  –   Number of embryos fertilized
  –   Number of embryos transferred
  –   Previous live birth
  –   Cause of infertility
Templeton & Morris 1998
2 vs. 3 Embryo Transfer???

• When greater than 4 embryos fertilized
  – 2 embryos has equal success to 3 in all ages


• Decreased twins by ~ 10% and almost 0%
  triplets
• Still had multiple rate that was ~ 30%
Double vs. Single Embryo Transfer

•   Martikainen et al Hum Repro 2001
•   Finland
•   RCT
•   144 pts
•   At least 4 good quality embryos
•   1st or 2nd IVF cycle
 Double vs.. Single Embryo Transfer

                              eSET    DET     P

+FH fresh                     32.4%   47.1%   NS
+FH frozen                    15%     16%     NS
Cumulative +FH                47.3%   58.6%   NS
Cumulative Live Birth         39%     51%     NS
Multiples                     5%      39%     0.01

 Martikainen et al Hum Repro 2001
Double vs.. Single Embryo Transfer

•   Lukassen et al Hum Repro 2005
•   Netherlands
•   RCT with 107 pts
•   2 cycles of eSET vs. 1 cycle DET
•   < 35 years
•   At least 2 embryos & 1 good quality
•   Stratified primary vs. secondary infertility
Double vs. Single Embryo Transfer
                           eSET   DET   P
 + FH 1st cycle            37%    47%   NS
 + FH 2nd cycle            25%          NS
 Live birth 1st cycle      26%    36%   NS
 Live birth 2nd cycle 20%
 Cumulative Live Birth     41%    36%   NS
 Multiples                 0%     37%   0.002

Lukassen et al Hum Repro 2005
Patient attitudes toward eSET vs. DET

• Højgaard et al Hum Reprod 2007
• Denmark
  – Common DET
  – 3 cycles limit to reimbursement
• Information given risks and chance of twins
• Anonymous Survey of 588 couples
  – 414 women
  – 404 men
Patient attitudes toward eSET vs. DET
• Højgaard et al Hum Reprod 2007

• 58.7% preferred twins
• Reason twins preferred
  – 23.3% wish for certainty of siblings
  – 22.5% positive attitude about twins
  – 19.3% fewer IVF treatments
  – 7.4% age plays a role
  – 1.9% few pregnancies as possible
     Patients’ view on Success

•   Twisk et al Fertility and Sterility 2007
•   Netherlands
•   244 women responded
•   Presented 4 scenarios
    – DET twin rate 25% in all scenarios
    – Pregnancy rate for eSET differed by 1,3 or 5%
        Patients’ view on Success

                                           Prefer eSET Prefer DET
eSET = DET                                 46%         54%
eSET 1% less effective                     36%         64%
(49% vs. 50%)
eSET 3% less effective                     24%         76%
(47% vs. 50%)
eSET 5% less effective                     15%         85%
(45% vs. 50%)
Twisk et al Fertility and Sterility 2007
  AART Halifax Results 2007

                 All Transfers   Day 3   Day 5

Singletons       63.9%           60%     64.3%

Twins            32.8%           31.4%   32.1%

Triplets/Quads   6.6%            8.6%    3.6%
Summary: 1, 2 or 3????
• Multiples pregnancies are high risk
• Risk of multiple birth is approx 35 to 40% in IVF
• eSET dramatically decreases multiple rate but
    with the cost of decreased pregnancy rate
•   Patients are not willing to accept even a small
    decrease in pregnancy rate
•   SO the question remains … 1 or 2 embryos???
Any Questions???????

				
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